Joon Min Jung

Cutaneous extranodal natural killer/T-cell lymphoma: A comparative clinicohistopathologic and survival outcome analysis of 45 cases according to the primary tumor site

BACKGROUND Differences in survival outcomes and prognostic factors of cutaneous extranodal natural killer/T-cell lymphoma (ENKTL) depending on primary tumor site are currently unknown. OBJECTIVE We sought to analyze the clinicopathological features and survival outcomes of cutaneous ENKTL according to primary tumor site. METHODS In all, 45 patients with cutaneous ENKTL were classified with: (1) primary cutaneous ENKTL, or (2) nasal ENKTL with cutaneous involvement. Clinicopathologic features, survival outcomes, and prognostic factors were analyzed using patients medical records. Survival outcomes were analyzed using the Kaplan-Meier method and compared using the log rank test. The Student t test, Fisher exact test, and linear by linear association test were used to analyze clinicopathologic differences between groups. RESULTS Clinical manifestations of cutaneous ENKTL included solitary or multiple subcutaneous nodules and cellulitis or abscess-like lesions. Primary cutaneous ENKTL demonstrated a less aggressive clinical course and better survival outcomes. The extent of cutaneous lesions demonstrated a significant effect on the prognosis of primary cutaneous ENKTL, but not on nasal ENKTL with cutaneous involvement. The presence of nasal lesions in primary cutaneous ENKTL was associated with poor prognosis. LIMITATIONS This study used a retrospective design and included a small sample size. CONCLUSION Although the clinicopathological features were similar regardless of subgroup, survival outcomes and prognostic factors differed depending on the primary tumor site of cutaneous ENKTL.

Iatrogenic Harlequin Syndrome: A New Case

Dear Editor: The Harlequin syndrome, first described by Lance et al.1 in 1988, represents an uncommon disorder of the sympathetic nervous system. It is characterized by unilateral diminished sweating and heat- or exercised-induced facial flushing. We present the case of one patient with this remarkable syndrome, including a review of the literature. A 43-year-old woman presented to our clinic with a peculiar pattern of facial flushing. She has been experiencing flushing and sweating on the left side of her face after physical exercise or after taking a hot bath (Fig. 1). The symptoms started about 2 years ago, after she had undergone an endoscopic surgery for the removal of a solitary pulmonary nodule. She has no other medical history besides chronic pancreatitis. She has never been treated for her symptoms before visiting our clinic. On examination at rest, no asymmetric facial flushing or sweating was noted. Neurological examination was normal, and signs of ptosis or miosis were absent. Laboratory tests, including complete blood count, erythrocyte sedimentation rate, glucose, sodium, potassium, and creatinine, revealed no abnormality. As the symptom had appeared only after the endoscopic surgery, we suspected that there might have been an accidental damage to the sympathetic nerve innervating the right facial area during the surgery. The patient was reassured of the benign nature of her complaints and was asked to avoid any aggravating factors. Most cases of Harlequin syndrome are primary in nature. This syndrome is most common in women, and social embarrassment is the main problem of affected persons. In about one-sixth of patients with Harlequin syndrome, the disorder is caused by an underlying disease or a structural lesion (i.e., secondary Harlequin syndrome). The iatrogenic type of Harlequin syndrome, like our case, is recently being reported with a higher frequency. Ten such cases have been reported: one occurring after internal jugular vein catheterization, five after paravertebral thoracic anesthetic blocks, three after surgical resection of a neck mass, and one after thoracic sympathectomy. Physicians should focus on taking the patients medical history for related factors such as a previous malignancy, as well as recent surgery or anesthesia-related problems. Clinical and neurological examinations are also required, and imaging techniques such as computed tomography or magnetic resonance imaging of the brain, spinal cord, and the carotid arteries and the lung apex should be performed to exclude the presence of a structural lesion. Usually, a patient with a primary or iatrogenic Harlequin syndrome does not need any treatment. If the symptoms are not acceptable, a contralateral sympathectomy may be considered2. Recently, a novel approach to the management of Harlequin syndrome, by using repeated stellate ganglion blocks, was proposed as a less invasive alternative treatment3. To our knowledge, a clinical presentation of Harlequin syndrome has not been previously reported in the Korean dermatological literature. We hope that this report would make dermatologists properly aware of this rare syndrome. Fig. 1 She experienced flushing on the left side of her face following physical exercise.

The antimycotic agent clotrimazole inhibits melanogenesis by accelerating ERK and PI3K-/Akt-mediated tyrosinase degradation

Azole antimycotic agents are known to have anti‐inflammatory and anti‐cancer effects, which are mediated through their effects on the p38‐cyclooxygenase‐2 (COX‐2)‐prostaglandin E2 (PGE2) pathway, as well as anti‐oxidant effects. Furthermore, pyridinyl imidazole compounds, such as SB203580 have recently been shown to inhibit melanogenesis. Accordingly, we hypothesized that azole antifungal agents might affect skin pigmentation. We herein investigated the effect of clotrimazole, the most commonly used azole antifungal agent, on melanogenesis. Intriguingly, clotrimazole reduced the melanin content in human melanocytes and mouse melanocytes, as well as in B16F10 mouse melanoma cells. Clotrimazole reduced levels of tyrosinase protein without altering mRNA expression. Simultaneous treatment with a proteasomal inhibitor restored both the suppression of melanin synthesis, and the downregulation of tyrosinase level, by clotrimazole. Clotrimazole also induced the phosphorylation of extracellular signal‐regulated kinase (ERK) and PI3K/Akt, while each inhibitor of these two signals abolished the decrease of melanin synthesis by clotrimazole. Thus, our data suggest that clotrimazole inhibits melanin synthesis by promoting the proteasomal degradation of tyrosinase, which is mediated through activation of the ERK and Akt signaling pathways. These results may indicate a new role for clotrimazole as a molecular‐mechanism‐based, safe depigmenting agent for topical management of hyper‐pigmentary sequelae related to fungal infection, or for other skin inflammatory disorders.

Development of Vitiligo during Treatment with Adalimumab: A Plausible or Paradoxical Response?

Dear Editor: Adalimumab is a complete human monoclonal anti-tumor necrosis factor α (anti-TNFα) that is generally well tolerated. With increasing use of adalimumab and other anti-TNFα therapies, several cutaneous adverse events have been reported during the therapy, including immune-mediated skin lesions1. A 39-year-old woman who had an 11-year history of Crohns disease and was treated with adalimumab (40 mg administered subcutaneously every other week) presented at our clinic with multiple achromic macules and patches on the extremities (Fig. 1). The lesions developed abruptly about 12 months after the initiation of adalimumab therapy. The diagnosis of vitiligo was made after the patients skin turned blue under a Woods lamp. Laboratory tests were also performed to check for other autoimmune conditions, including thyroid disorders, and no abnormality was diagnosed. The patient denied any family history of vitiligo. She has been treated with a combination therapy of excimer laser and topical tacrolimus without stopping the adalimumab therapy for about 1 year, and has shown minimal response thus far. Fig. 1 Multiple well-demarcated irregularly shaped depigmented macules and patches (A) on the left proximal thigh, (B) dorsum of the right foot, (C) dorsum of the right hand, and (D) right forearm. The role of anti-TNFα inhibitors in the development of vitiligo is complicated and contradictory. There have been several case reports that showed improvement in vitiligo in patients receiving anti-TNFα therapy for other diseases2. The therapeutic effect of anti-TNFα inhibitors on vitiligo might result from stopping the physiological effect of TNFα on melanogenesis. Concretely, it has been reported that TNFα decreases the level of tyrosinase, a rate-limiting enzyme in melanin biosynthesis in vitro3. The melanocytotoxic effect of TNFα in vitiligo has also been demonstrated2. On the contrary, anti-TNFα inhibitors have been associated with the development of a considerable number of autoimmune diseases such as vitiligo, as well as leukocytoclastic vasculitis, systemic lupus erythematosus, psoriasis-like lesions, and alopecia areata1. Several theories were proposed to explain the mechanisms underlying the development of autoimmunity during treatment with anti-TNFα inhibitors. In vivo, nucleosome numbers (major autoantigens released during apoptosis) increase in patients receiving anti-TNFα therapies. This could lead to the subsequent induction of autoantibodies4. To our knowledge, only two cases of vitiligo have been attributed to adalimumab use. The first case was that of newly developed vitiligo after 8 months of adalimumab therapy for Crohns disease; this was similar to our case5. In the second case, there was rapid deterioration of vitiligo within 3 months of adalimumab therapy for managing ankylosing spondylitis4. In our case, it could not be determined whether vitiligo was caused by adalimumab therapy or if it developed in association with Crohns disease because the concomitant occurrence of vitiligo with inflammatory bowel disease has been rarely reported. The long duration of Crohns disease, and the sudden onset and rapid spreading of cutaneous lesions support the former possibility. Previous reports and our case suggest that anti-TNFα agents, including adalimumab, can induce vitiligo development. Dermatologists should be aware of this possibility for an earlier detection and treatment of vitiligo in patients receiving anti-TNFα therapy.

Histopathological Analysis of 226 Patients With Rosacea According to Rosacea Subtype and Severity.

Background:The histopathological features of rosacea have not been described in detail. Objective:To evaluate the histopathological features of rosacea according to clinical characteristics such as subtype and severity. Methods:We retrospectively analyzed histopathological findings in 226 patients with rosacea, which included 52 patients with the erythematotelangiectatic rosacea (ETR) and 174 patients with the papulopustular rosacea (PPR) subtype. The frequency of each histopathological finding was compared between subtypes. Histopathological features were also compared according to the severity, through subgroup analysis within each subtype group. Results:Perivascular and perifollicular lymphohistiocytic infiltration were common dermal findings in both subtype groups, but the intensity of dermal inflammatory infiltration was higher in PPR than in ETR. Follicular spongiosis and exocytosis of inflammatory cells into hair follicles were noted in both subtypes; but these findings were significantly more common in the PPR subtype. Vascular changes (telangiectasia and proliferation) and solar elastosis were common histopathological findings in both subtypes, with no difference in frequency between subtype groups. Demodex mites were identified in about 40% of patients, and the frequency of demodex mites did not differ between subtype groups. The intensity of perifollicular inflammation and the presence of follicular inflammatory reactions were dependent on the severity of rosacea in both subtype groups. Conclusions:The intensity of inflammatory reactions, especially perifollicular infiltration, was higher in PPR patients than in ETR patients. Rosacea has a spectrum of histopathological features that are related to clinical progression between rosacea subtypes.

Clinical Evaluation of 368 Patients with Nasal Rosacea: Subtype Classification and Grading of Nasal Rosacea

Background: The clinical features of nasal rosacea have not been described in detail. Objective: To describe the clinical features of nasal rosacea. Methods: 599 patients were classified into those with rosacea in both the nasal and extra-nasal areas (group A), localized nasal rosacea (group B) and rosacea without nasal involvement (group C). Results: The mixed subtype was more common in group A (n = 337) than in group C (n = 231). The severity score was higher in group A than in group C. Erythematotelangiectatic rosacea was the most common subtype in group B (n = 31) and was more common in group B than in group A. Rosacea mainly affected the lower half of the nose in group B, but affected the entire nose in group A. Conclusion: Nasal involvement may be an index of severe rosacea. Localized nasal rosacea is a separate spectrum with different clinical features.

Dopamine D4 receptor antagonist inhibits melanogenesis through transcriptional downregulation of MITF via ERK signalling

Keywords: 667 trihydrochloride; dopamine D4 receptor antagonist; extracellular signal-regulated kinase; L-750; melanogenesis; microphthalmia-associated transcription factor

A case of anaplastic large‐cell lymphoma mimicking preseptal cellulitis

mutation in the corneodesmosin gene in a Mexican family with hypotrichosis simplex of the scalp. Br J Dermatol 2005; 153: 1216–19. 3 Huang XS, Jiang HO, Quan QL. Clinical investigation of a Chinese family with hypotrichosis simplex of the scalp and mutational analysis of CDSN gene. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2012; 29: 452–4. 4 Capon F, Allen MH, Ameen M et al. A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups. Hum Mol Genet 2004; 13: 2361–8. 5 Israeli S, Zamir H, Sarig O et al. Inflammatory peeling skin syndrome caused by a mutation in CDSN encoding corneodesmosin. J Invest Dermatol 2011; 131: 779–81.

Acquired bilateral telangiectasia macularis eruptiva perstans: A unique clinical feature of photodamaging rather than a subtype of cutaneous mastocytosis

Telangiectasia macularis eruptiva perstans (TMEP) is a rare subtype of cutaneous mastocytosis, characterized by telangiectatic tan to brown macules on the trunk and extremities. Although TMEP has been descried as an uncommon disease in the literature, we often encounter patients with TMEP lesions in the outpatient clinic. We aimed to assess the clinical and histopathological characteristics of acquired bilateral TMEP, and the pathophysiological mechanism of acquired bilateral TMEP among these patients. We retrospectively reviewed 30 patients (28 men and 2 women) with acquired bilateral TMEP; multiple telangiectatic dark red to brown macules that were symmetrically distributed. The clinical characteristics and general histopathological findings of lesional skin were investigated. The number of mast cells was evaluated using immunohistochemical analysis with an antibody directed against c‐kit (CD117). Acquired bilateral TMEP was predominantly localized on the sun‐exposed area: the upper arm in 30 patients (100%), forearm in 19 patients (63.3%) and anterior chest in 15 patients (50%). A total of 16 patients (53.3%) showed at least one aggravating factor, including UV irradiation, alcohol use and heat exposure. Compared with the mast cell numbers in 19 age‐ and biopsy site‐matched healthy controls (91 ± 29.0/mm2), the number of mast cells in the papillary dermal skin of acquired bilateral TMEP patients was significantly increased (159 ± 37.2/mm2, P < 0.01). In addition, a significant difference in vessel numbers in the papillary dermis was observed between acquired bilateral TMEP patients and healthy controls (10.5 ± 1.9 vs 5.4 ± 1.0/mm2, P < 0.01). Acquired bilateral TMEP is a relatively common disorder in middle‐aged Asian men. An increased number of mast cells and dilated vessels might be a photoaging‐related reactive process of chronic sun‐exposure, which consequently leads to the formation of characteristic telangiectatic hyperpigmentary macules through certain melanogenic mediators.

Histological and molecular analysis of the long-pulse 1,064-nm Nd:YAG laser irradiation on the ultraviolet-damaged skin of hairless mice: In association with pulse duration change

Background: Nonablative lasers have been widely used to improve photodamaged skin, although the mechanism underlying dermal collagen remodeling remains unclear. Objective: To investigate the effects and the molecular mechanisms of long-pulse neodymium-doped yttrium aluminum garnet (Nd:YAG) laser irradiation on dermal collagen remodeling in association with different pulse durations. Material and methods: Five hairless mice were pretreated with ultraviolet B irradiation for 8 weeks. The dorsal quadrant of each mouse was then irradiated twice at 1-week intervals at a pulse duration of 1 ms, 12 ms, or 50 ms, and a constant fluence of 20 J/cm2. The levels of dermal collagen, mRNAs of procollagens, matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), and various growth factors were analyzed after 4 weeks. Results: Long-pulse Nd:YAG treatment increased the dermal collagen level. A substantial increase in the level of procollagens, MMPs, TIMPs, and various growth factors was also observed irrespective of pulse duration, with a trend toward maximal increase at a pulse duration of 12 ms. Conclusion: Long-pulse 1,064-nm Nd:YAG laser irradiation promotes wound-healing process, which is characterized by the induction of growth factor expression and subsequent increase in MMPs and TIMPs, followed by matrix remodeling as confirmed by new procollagen production.